应用实时荧光定量方法研究实验用小型猪细胞色素P450的表达
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摘要
本研究通过采用T-A克隆技术构建出猪CYP1A1、2A19、2D25、2E1、3A29和β-actin基因的重组质粒作为定量标准品，建立一套适合于研究猪CYPs mRNA表达水平的实时荧光定量方法，并以猪体内最为重要的药物代谢关键酶基因CYP3A29为基础，以商品猪——荣昌猪为对照，对4-6月龄的巴马香猪、贵州小型猪肝脏表达水平进行定量，初步筛选与人肝CYP3A4 mRNA水平接近的实验用小型猪品系。然后进一步对该品系小型猪初生、断奶、性成熟、体成熟以及2周年的肝脏表达水平进行定量，筛选到该品系猪与人肝CYP3A4 mRNA水平接近年龄段。最后，对筛选到的特定小型猪CYP1A1、2A19、2D25、2E1、3A29 mRNA表达的组织分布、以及人CYP3A4的典型诱导剂——利福平对其肝脏CYP3A29 mRNA表达的诱导作用进行研究，并将结果与报道的人CYPs mRNA对应情况进行比较，获得的主要结果如下：
1．建立了适用于定量猪CYPs mRNA表达水平的TaqMan方法。PCR反应总体积为10μL，各成分终浓度为：Buffer，1×；Mg2+，5.5 mmol／L；dNTP mix，0.8 mmol／L；上、下游引物，各0.3μmol／L；rTaq，0.2 U／μL；探针0.1μmol／L；模板，1μL。PCR热循环条件为94℃5 min→40 cycles(94℃15 s→60℃45 s→读板)。所建立的TaqMan方法定量范围较广、扩增效率较高、重复性较好。
2．4-6月龄巴马香猪、贵州小型猪、荣昌猪肝脏CYP3A29 mRNA平均表达水平分别为35.36±14.69、21.48±11.87和38.87±20.11，与人肝对应酶CYP3A4水平接近。从转录水平表明，以上3种猪均可用作人CYP 3A4所代谢药物的安全性评价实验模型。
3．巴马香猪CYP3A29 mRNA主要在肝脏中表达，其水平在初生到断奶、断奶到性成熟阶段均有显著增加，至性成熟及体成熟时其值分别为16.7243908±8.17834582和29.76705722±18.73595974，与人肝CYP3A4水平接近。从转录水平表明，性成熟及体成熟巴马香猪均可用作人CYP 3A4所代谢药物的安全性评价动物模型。
4．体成熟巴马香猪CYP1A1、2A19、2D25、2E1 mRNA水平均以肝脏最高，其值分别为13.24145753±9.166365249、134.5902182±68.02425634、33.43790049±43.12612521和162.783024±208.8879079，均与人肝对应酶CYP1A2、2A6、2D6、2E1水平差异较大。从转录水平表明，体成熟巴马香猪不是人CYP1A2、2A6、2D6以及2E1所代谢药物安全性评价的理想实验模型。
5．利福平能够显著增加体成熟巴马香猪肝脏CYP3A29 mRNA的表达，其水平提高了7.71倍，而对CYP1A1、2A19、2D25、2E1 mRNA表达无影响。从诱导的层次表明，体成熟巴马香猪可用作人CYP 3A4所代谢药物的安全性评价动物模型。
According to cloning standards and screening TaqMan PCR system, quantitativereal-time RT-PCR method suitable for studying expression revels of CYPs mRNA wasestablished and used to evaluate the feasibility of experimental miniature pigs' livers usingas model of security estimate of drug by quantitation expression livers of CYP3A29 mRNAin livers of 4-6 months old Bama miniature pigs, Guizhou miniature pigs and Rongchangpigs. Then, CYP3A29 mRNA in livers of 0, 40, 120, 180 and 720 days old experimentalminiature pigs seclected according to screening 3 breeds of pigs were quantitated, and theages during which the expression levels of CYP3A29 mRNA in experimental miniaturepigs'livers are close to that of CYP3A4 in human livers. Tissue distribution of CYP1A1,2A19, 2D25, 2E1 and 3A29 mRNA expression, and the effect of rifampicin on CYP3A29mRNA of livers were studied with these screening experimental miniature pigs. Thefollowing was concluded after comparing these results to that of human counterpartdocumented:
1. Real-time RT-PCR method for quantitation expression levels of CYPs mRNA inpigs was established. Total volume of PCR was 10μL, including 1×Buffer、5.5 mmol/LMg~(2+)、0.8 mmol/L dNTP mix、0.3μmol/L each primer、0.2 U/μL rTaq、0.1μmol/L probeand 1μL template. PCR was conducted by 94℃5 min→40 cycles(94℃15 s→60℃45s→read panel). This method had good properties of broad rang of quantitation, highefficiency of amplification and good repetition of determination.
2. The average expression levels of CYP3A29 mRNA in livers of 4-6 months old ofBama miniature pigs, Guizhou miniature pigs and Rongchong pigs were 35.36±14.69、 21.48±11.87 and 38.87±20.11, respectively. These values were close to that of humanlivers' CYP3A4 that was the conterpart of pig's CYP3A29 in human body. This resultindicated transcriptionally that 4-6 months old of Bama miniature pigs, Guizhou miniaturepigs and Rongchong pigs were all suitable for experimental model of security estimate ofdrug metabolismed by human CYP3A4.
3. liver had the highest level of CYP3A29 mRNA than the other tissues in Bamaminiature pigs. There were remarkable increase of CYP3A29 mRNA levels in Bamaminiature pigs' livers from 1-40 days and 40-120 days. The average expression levels ofCYP3A29 mRNA in livers of 120 days(sexual mature) and 180 days(bodily mature) old ofBama miniature pigs were 16.7243908±8.17834582 and 29.76705722±18.73595974,respectively. These values were close to that of human livers' CYP3A4. These resultsindicated transcriptionally that sexual mature and bodily mature of Bama miniature pigswere all suitable for animal model of security estimate of drug metabolismed by humanCYP3A4.
4. liver had the highest level of CYP1A1, 2A19, 2D25 and 2E1 mRNA than the othertissues in bodily mature of Bama miniature pigs. The average expression levels were13.24145753±9.166365249, 134.5902182±68.02425634, 33.43790049±43.12612521 and162.783024±208.8879079, respectively. These values were quite large different from thatof human livers' CYP1A2, 2A6, 2D6 and 2E1 that was the counterparts of pig's CYP1A1,2A19, 2D25 and 2E1 in human body. These results indicated transcriptionally that bodilymature of Bama miniature pigs were not idea animal models of security estimate of drugsmetabolismed by human CYP1A2, 2A6, 2D6 or 2E1.
5. The average expression levels of CYP3A29 mRNA in livers of bodily mature ofBama miniature pigs icreased remarkablely treated with rifampicin, and the value was 7.71times of that of untreated bodily mature of Bama miniature pigs. Expression levels ofCYP1A2, 2A6, 2D6 and 2E1 mRNA were all not affected by treatition of rifampicin. Thisresult indicated induciablely that bodily mature of Bama miniature pigs were all suitablefor experimental model of security estimate of drug metabolismed by human CYP3A4.
1．建立了适用于定量猪CYPs mRNA表达水平的TaqMan方法。PCR反应总体积为10μL，各成分终浓度为：Buffer，1×；Mg2+，5.5 mmol／L；dNTP mix，0.8 mmol／L；上、下游引物，各0.3μmol／L；rTaq，0.2 U／μL；探针0.1μmol／L；模板，1μL。PCR热循环条件为94℃5 min→40 cycles(94℃15 s→60℃45 s→读板)。所建立的TaqMan方法定量范围较广、扩增效率较高、重复性较好。
2．4-6月龄巴马香猪、贵州小型猪、荣昌猪肝脏CYP3A29 mRNA平均表达水平分别为35.36±14.69、21.48±11.87和38.87±20.11，与人肝对应酶CYP3A4水平接近。从转录水平表明，以上3种猪均可用作人CYP 3A4所代谢药物的安全性评价实验模型。
3．巴马香猪CYP3A29 mRNA主要在肝脏中表达，其水平在初生到断奶、断奶到性成熟阶段均有显著增加，至性成熟及体成熟时其值分别为16.7243908±8.17834582和29.76705722±18.73595974，与人肝CYP3A4水平接近。从转录水平表明，性成熟及体成熟巴马香猪均可用作人CYP 3A4所代谢药物的安全性评价动物模型。
4．体成熟巴马香猪CYP1A1、2A19、2D25、2E1 mRNA水平均以肝脏最高，其值分别为13.24145753±9.166365249、134.5902182±68.02425634、33.43790049±43.12612521和162.783024±208.8879079，均与人肝对应酶CYP1A2、2A6、2D6、2E1水平差异较大。从转录水平表明，体成熟巴马香猪不是人CYP1A2、2A6、2D6以及2E1所代谢药物安全性评价的理想实验模型。
5．利福平能够显著增加体成熟巴马香猪肝脏CYP3A29 mRNA的表达，其水平提高了7.71倍，而对CYP1A1、2A19、2D25、2E1 mRNA表达无影响。从诱导的层次表明，体成熟巴马香猪可用作人CYP 3A4所代谢药物的安全性评价动物模型。
According to cloning standards and screening TaqMan PCR system, quantitativereal-time RT-PCR method suitable for studying expression revels of CYPs mRNA wasestablished and used to evaluate the feasibility of experimental miniature pigs' livers usingas model of security estimate of drug by quantitation expression livers of CYP3A29 mRNAin livers of 4-6 months old Bama miniature pigs, Guizhou miniature pigs and Rongchangpigs. Then, CYP3A29 mRNA in livers of 0, 40, 120, 180 and 720 days old experimentalminiature pigs seclected according to screening 3 breeds of pigs were quantitated, and theages during which the expression levels of CYP3A29 mRNA in experimental miniaturepigs'livers are close to that of CYP3A4 in human livers. Tissue distribution of CYP1A1,2A19, 2D25, 2E1 and 3A29 mRNA expression, and the effect of rifampicin on CYP3A29mRNA of livers were studied with these screening experimental miniature pigs. Thefollowing was concluded after comparing these results to that of human counterpartdocumented:
1. Real-time RT-PCR method for quantitation expression levels of CYPs mRNA inpigs was established. Total volume of PCR was 10μL, including 1×Buffer、5.5 mmol/LMg~(2+)、0.8 mmol/L dNTP mix、0.3μmol/L each primer、0.2 U/μL rTaq、0.1μmol/L probeand 1μL template. PCR was conducted by 94℃5 min→40 cycles(94℃15 s→60℃45s→read panel). This method had good properties of broad rang of quantitation, highefficiency of amplification and good repetition of determination.
2. The average expression levels of CYP3A29 mRNA in livers of 4-6 months old ofBama miniature pigs, Guizhou miniature pigs and Rongchong pigs were 35.36±14.69、 21.48±11.87 and 38.87±20.11, respectively. These values were close to that of humanlivers' CYP3A4 that was the conterpart of pig's CYP3A29 in human body. This resultindicated transcriptionally that 4-6 months old of Bama miniature pigs, Guizhou miniaturepigs and Rongchong pigs were all suitable for experimental model of security estimate ofdrug metabolismed by human CYP3A4.
3. liver had the highest level of CYP3A29 mRNA than the other tissues in Bamaminiature pigs. There were remarkable increase of CYP3A29 mRNA levels in Bamaminiature pigs' livers from 1-40 days and 40-120 days. The average expression levels ofCYP3A29 mRNA in livers of 120 days(sexual mature) and 180 days(bodily mature) old ofBama miniature pigs were 16.7243908±8.17834582 and 29.76705722±18.73595974,respectively. These values were close to that of human livers' CYP3A4. These resultsindicated transcriptionally that sexual mature and bodily mature of Bama miniature pigswere all suitable for animal model of security estimate of drug metabolismed by humanCYP3A4.
4. liver had the highest level of CYP1A1, 2A19, 2D25 and 2E1 mRNA than the othertissues in bodily mature of Bama miniature pigs. The average expression levels were13.24145753±9.166365249, 134.5902182±68.02425634, 33.43790049±43.12612521 and162.783024±208.8879079, respectively. These values were quite large different from thatof human livers' CYP1A2, 2A6, 2D6 and 2E1 that was the counterparts of pig's CYP1A1,2A19, 2D25 and 2E1 in human body. These results indicated transcriptionally that bodilymature of Bama miniature pigs were not idea animal models of security estimate of drugsmetabolismed by human CYP1A2, 2A6, 2D6 or 2E1.
5. The average expression levels of CYP3A29 mRNA in livers of bodily mature ofBama miniature pigs icreased remarkablely treated with rifampicin, and the value was 7.71times of that of untreated bodily mature of Bama miniature pigs. Expression levels ofCYP1A2, 2A6, 2D6 and 2E1 mRNA were all not affected by treatition of rifampicin. Thisresult indicated induciablely that bodily mature of Bama miniature pigs were all suitablefor experimental model of security estimate of drug metabolismed by human CYP3A4.
引文
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